WO2024057249A1 - Procédé amélioré pour la préparation de composés à base de sulfonylurée - Google Patents
Procédé amélioré pour la préparation de composés à base de sulfonylurée Download PDFInfo
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- WO2024057249A1 WO2024057249A1 PCT/IB2023/059133 IB2023059133W WO2024057249A1 WO 2024057249 A1 WO2024057249 A1 WO 2024057249A1 IB 2023059133 W IB2023059133 W IB 2023059133W WO 2024057249 A1 WO2024057249 A1 WO 2024057249A1
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- WIPO (PCT)
- Prior art keywords
- compound
- solvent
- formula
- dissolved
- potassium
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 245
- 238000000034 method Methods 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 65
- 229940100389 Sulfonylurea Drugs 0.000 title abstract description 7
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 title abstract description 7
- 239000002904 solvent Substances 0.000 claims description 120
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 105
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 104
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 102
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 100
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 95
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 75
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 66
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 66
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 61
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 60
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 51
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 43
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 42
- 239000011541 reaction mixture Substances 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 36
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 33
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 30
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 27
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 25
- -1 vitride Substances 0.000 claims description 25
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 22
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 22
- 229960004132 diethyl ether Drugs 0.000 claims description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- 229940086542 triethylamine Drugs 0.000 claims description 18
- 239000012973 diazabicyclooctane Substances 0.000 claims description 16
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 16
- 229960004592 isopropanol Drugs 0.000 claims description 16
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 claims description 15
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 15
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 15
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 14
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 13
- 239000012312 sodium hydride Substances 0.000 claims description 13
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 12
- 239000011736 potassium bicarbonate Substances 0.000 claims description 12
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 12
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 12
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 12
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 239000012279 sodium borohydride Substances 0.000 claims description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 9
- CQODGVQBRIGKLJ-UHFFFAOYSA-L [Na+].[Na+].[O-]OOO[O-] Chemical compound [Na+].[Na+].[O-]OOO[O-] CQODGVQBRIGKLJ-UHFFFAOYSA-L 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 9
- 239000000920 calcium hydroxide Substances 0.000 claims description 9
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 9
- 150000002170 ethers Chemical group 0.000 claims description 9
- 229940052303 ethers for general anesthesia Drugs 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 9
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 235000011116 calcium hydroxide Nutrition 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 239000012027 Collins reagent Substances 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 238000006859 Swern oxidation reaction Methods 0.000 claims description 3
- 229940117975 chromium trioxide Drugs 0.000 claims description 3
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 3
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 2
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 2
- 125000004001 thioalkyl group Chemical group 0.000 claims description 2
- 150000003573 thiols Chemical class 0.000 claims description 2
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 claims 1
- 239000011651 chromium Substances 0.000 claims 1
- 229960004756 ethanol Drugs 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 12
- 239000000126 substance Substances 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 27
- HAMGPBKPACGWND-ZOXUKVPXSA-N 1-[(E)-2-[(2R)-1,2-dimethylpyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound CN1[C@@](CCC1)(C)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O HAMGPBKPACGWND-ZOXUKVPXSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 239000010410 layer Substances 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- JHWUNBMMLDCHCY-IVYUTVGYSA-N tert-butyl (2R)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@@]1(N(CCC1)C(=O)OC(C)(C)C)C JHWUNBMMLDCHCY-IVYUTVGYSA-N 0.000 description 8
- AHXRXGFJKWRVIZ-DPCFLFMUSA-N tert-butyl (2R)-2-methyl-2-[(E)-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoyl]ethenyl]pyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)NS(=O)(=O)/C=C/[C@@]1(N(CCC1)C(=O)OC(C)(C)C)C AHXRXGFJKWRVIZ-DPCFLFMUSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- YQXRKJHVAUKXRN-LLVKDONJSA-N (2r)-2-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@]1(C)C(O)=O YQXRKJHVAUKXRN-LLVKDONJSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- JCXLZWMDXJFOOI-WCCKRBBISA-N ethyl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CCOC(=O)[C@H](C)N JCXLZWMDXJFOOI-WCCKRBBISA-N 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229940124530 sulfonamide Drugs 0.000 description 5
- IAZFNKZRJHARAP-LLVKDONJSA-N tert-butyl (2R)-2-formyl-2-methylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@]1(C)C=O IAZFNKZRJHARAP-LLVKDONJSA-N 0.000 description 5
- APLKPAQPQLXCRO-CYBMUJFWSA-N 1-o-tert-butyl 2-o-ethyl (2r)-2-methylpyrrolidine-1,2-dicarboxylate Chemical compound CCOC(=O)[C@@]1(C)CCCN1C(=O)OC(C)(C)C APLKPAQPQLXCRO-CYBMUJFWSA-N 0.000 description 4
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 description 4
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- VTUUHTGTUIJRSA-LLVKDONJSA-N tert-butyl (2r)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@]1(C)CO VTUUHTGTUIJRSA-LLVKDONJSA-N 0.000 description 4
- CCRYUSZLTXBJGF-ZAHGZRRWSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-2-methylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@]1(NCCC1)C CCRYUSZLTXBJGF-ZAHGZRRWSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/57—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton
- C07C211/61—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton with at least one of the condensed ring systems formed by three or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
Definitions
- the present invention relates to an improved process for the preparation of sulfonylurea based compounds of general formula (I). More specifically present invention provides an improved process for the preparation of compound of formula (I-a). Present invention also provides some novel impurities generated during process.
- NLRP3 modulators which are useful in the treatment of the diseases or conditions mediated by NLRP3 or conditions in which interleukin 1 ⁇ activity is implicates. This includes inflammation, cryopyrin-associated periodic syndrome (CAPS), gouty arthritis, multiple sclerosis, inflammatory bowel diseases, Parkinson’s and Alzheimer’s diseases and other diseases related to Central Nervous System.
- NLRP3 modulators preferably useful as therapeutics in treatment of a variety of pathological condition including but not limited to lymphoma, autoimmune diseases, cancer, inflammatory diseases, neurodegenerative diseases or conditions.
- the present invention discloses an improved process for the preparation of sulfonylurea based compounds of general formula (I). More specifically invention provides an improved process for the preparation of compound of formula (I-a). Present invention also provides some novel impurities generated during process.
- the compounds prepared by this method are useful for the diseases or conditions mediated by NLRP3 or conditions in which interleukin 1 ⁇ activity is implicates.
- the present invention provides a process for the preparation of compound of formula (I)
- the present invention provides a process for the preparation of compound of following formula (I- a).
- the present invention provides a crystalline form of compound of formula (I- a). In another embodiment, the present invention provides a process for the preparation of crystalline form of compound of formula (I-a).
- the present invention provides a process for the preparation of amorphous form of compound of formula (I-a).
- the present invention encompasses compounds having chemical name (R,E)-2-( 1 ,2-dimethylpyrrolidin-2-yl)-N-(( 1 ,2,3 ,7-tetrahydro-s-indacen-4-yl)carbamoyl)ethene- 1-sulfonamide (Compound A), (R)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethane- 1 -sulfonamide (Compound B), chemical name 3-( 1,2, 3, 5,6,7- hexahydro-s-indacen-4-yl)- 1,1 -dimethylurea ( Compound C), chemical name l,3-bis(l,2,3,5,6,7- hexahydro-s-indacen-4-yl)urea (Compound D), chemical name
- the compound of formula (A) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (B) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (C) is controlled in formula (I-a) with the limit of 0.01% to 2.0%. In another embodiment the compound of formula (D) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (E) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (F) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (G) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (H) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (I) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (J) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- Figure 1 is the Powder X-ray Diffraction pattern of crystalline Form I of (R,E)-2-(l,2- dimethylpyrrolidin-2-yl)-N-(( 1,2, 3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-l- sulfonamide (compound I-a).
- Figure 2 is the Powder X-ray Diffraction pattern of crystalline Form II of (R,E)-2-(l,2- dimethylpyrrolidin-2-yl)-N-(( 1,2, 3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-l- sulfonamide (compound I-a).
- Figure 3 is the Powder X-ray Diffraction pattern of crystalline Form III of (R,E)-2-(l,2- dimethylpyrrolidin-2-yl)-N-(( 1,2, 3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-l- sulfonamide (compound I-a).
- Figure 4 is the Powder X-ray Diffraction pattern of amorphous form (R,E)-2-(l,2- dimethylpyrrolidin-2-yl)-N-(( 1,2, 3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-l- sulfonamide (compound I-a).
- CDCI3 Deuterated chloroform
- Spray drying was done on LAB SPRAY DRYER, LU 222 ADVANCED, SD-1000
- the ‘aryl’ group used either alone or in combination with other radicals is selected from a suitable aromatic system containing one two or three rings wherein such ring may be attached together in pendant manner or may be fused, more preferably the groups are selected from optionally substituted phenyl, naphthyl, tetrahydronaphthyl, biphenyl and the like;
- the ‘alkyl’ group either used alone or in combination with other radicals denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like;
- the ‘alkoxy’ refers to the straight or branched chain alkoxides of the number of carbon atoms specified.
- the ‘cycloalkyl’ group used either alone or in combination with other radicals is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like;
- haloalkyl means an alkyl structure in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another.
- the “haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like;
- the ‘heteroaryl’ means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to other kinds of ring’s, such as aryls, cycloalkyls, and heterocycles that are not aromatic.
- the halogen atoms are not all the same as one another;
- heterocyclyl means a saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, further optionally including the oxidized forms of sulfur, namely SO & SO 2 Heterocyclyl systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated.
- the above and other objects of the present invention are attained as described herein below.
- the objects are attained by the improved process for the preparation of sulfonylurea based compounds of the formula (I) and intermediates thereof as described herein.
- B described above may be selected from following ring system: where in X, Y, Z at each occurrence independently represents C, N, S, SO 2 , and O, which may be optionally substituted;
- R 1 at each occurrence independently represents hydrogen, halogen, haloalkyl optionally substituted groups selected from (C 1 -C 6 )alkyl;
- R at each occurrence independently represents hydrogen, halogen, haloalkyl, optionally substituted groups selected from (C 1 -C 6 )alkyl;
- R 3 and R 4 at each occurrence independently represents hydrogen
- X is N-R 5 ; O, S, SO 2 ;
- R 5 at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkylSO 2 (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylN(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylN(C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercaptoalkyl, SO 2 (Ci- C 6
- the present invention provides an improved process for the preparation of compound of formula (I) as described in Scheme - 3:
- Step - 1 Preparation of compound (III) Reacting compound (II) with thionyl chloride in presence of one or more solvents to obtain compound of formula (III).
- the organic solvent used in step - 1 is selected from methanol, ethanol, isopropyl alcohol, n-butanol, ethyl acetate, toluene, tetrahydrofuran, diisopropyl ether, methyl tertiary butyl ether and the like.
- one or more solvent used in step - 2 is selected from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, n-hexane, n- heptane and the like.
- the base used in step - 2 is selected from N,N-diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, DBU, DBN, DABCO and the like.
- the base used in step - 3 is selected from imidazole, N,N-diisopropylethylamine, triethylamine, pyridine, DBU, DBN, DABCO and the like.
- One or more solvent used in step - 4 is selected from dimethyl sulfoxide, dimethylformamide, toluene, tetrahydrofuran, 1,4-dioxane, dimethyl ether, Acetone, n-hexane, n-heptane and the like.
- the base used in step - 4 is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, or sodium pentoxide, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodamide and the like.
- one or more solvent used in step - 5 is selected from water, methanol, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, acetonitrile, ethyl acetate, toluene, dichloromethane, n-hexane, n-heptane and the like.
- the base used in step - 5 is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tertiarybutoxide, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodamide and the like.
- Part-A Reacting compound (VII) with isobutyl chloroformate in presence of base and one or more solvent to obtain filterate;
- Part-B Sodium borohydride is dissolved in one or more solvent. Adding filterate obtained from Part-A to the reaction mixture to obtain compound (VIII).
- one or more solvent used in step - 6 is selected from ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert -butyl ether, water, ethyl acetate and the like.
- the base used in step - 6 is selected N-methyl morpholine, N,N-Diisopropylethyl amine, triethyl amine, pyridine, DBU, DBN, DABCO and the like.
- one or more solvent used in step-7 is selected from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, n-hexane, n-heptane, cyclohexane and the like.
- the oxidizing agents used in step-7 is selected from pyridinium chloro chromate, Pyridinium Dichromate, chromium trioxide, Collins reagent, Swern oxidation and the like.
- Compound (IX) is dissolved in one or more solvent in presence of base.
- Compound (X) is dissolved in one or more solvent and obtained solution was adding in the mixture of compound (IX) to obtain compound (XI).
- one or more solvent used in step - 8 is selected from N,N-dimethylformamide, dimethylsulfoxide, toluene, ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, methyl tert-butyl ether and the like.
- the base used in step - 8 is selected from sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydride, potassium tert-butoxide or sodium pentoxide and the like.
- one or more solvent used in step - 9 is selected from dimethylformamide, dimethylsulfoxide, toluene, ethers, methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t- butyl alcohol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether, n-hexane, n-heptane and the like.
- Suitable temperature used in step - 9 is 50°C to 100°C.
- Compound (XII) is dissolved in one or more solvent in present of base.
- Compound (XIII) is dissolved in one or more solvent and obtained solution was adding dropwise in the mixture of compound (XII) to obtain compound (XIV).
- one or more solvent used in step - 10 is selected from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, cyclohexane, n- hexane and the like.
- the base used in step - 10 is selected from N-methyl morpholine, N,N-Diisopropylethylamine, triethyl amine, N,N-diisopropylethylamine, pyridine, DBU, DBN, DABCO, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydride, potassium tert-butoxide, or sodium pentoxide and the like.
- Compound (XIV) is dissolved in one or more solvent. Adding reagent in a mixture of compound (XIV) to obtain compound (XV).
- one or more solvent used in step - 11 is selected from dichloromethane, dichloroethane, chlorobenzene, toluene, xylene, ethylbenzene, pentane, n-hexane, n-heptane, cyclohexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethylether, methyl-tert-butyl ether, ethyl acetate, tetrahydrofuran, acetone, N,N-dimethylformamide, water and the like.
- the reagent used in step - 11 is selected from trifluoroacetic acid, hydrochloric acid, Methane sulphonic acid, Acetic acid, formic acid and the like.
- Compound (XV) is dissolved in one or more solvent in presence of base and reagent. Adding one or more reagent to the reaction mixture of compound (XV) to obtain compound (I).
- one or more solvent used in step - 12 is selected from water, dichloromethane, dichloroethane, chlorobenzene, toluene, xylene, ethylbenzene, pentane, n-hexane, n-heptane, cyclohexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethylether or methyl tertiary butyl ether and the like.
- the base, used in step - 12 is selected from triethylamine, N,N-diisopropylethylamine, pyridine, DBU, DBN, DABCO and the like.
- the reagent used in step - 12 is selected from p-formaldehyde, sodium borohydride, Pd/C, Raney nickel, vitride, or lithium aluminium hydride and the like.
- one or more solvent used in purification is selected from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, water, dimethylformamide, n-hexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether and the like.
- the invention provides an improved process for the preparation of compound of formula (I-a) as described in Scheme - 3:
- Step 1-a Preparation of compound (Ill-a)
- the organic solvent used in step 1-a is selected from methanol, ethanol, isopropyl alcohol, n-butanol, ethyl acetate, toluene, tetrahydrofuran, diisopropyl ether, methyl tertiary butyl ether and the like.
- Preferred solvent are selected from methanol, ethanol, diisopropyl ether.
- one or more solvent used in step 2-a is selected from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, n-hexane, n- heptane and the like.
- Preferred solvent are selected from acetonitrile and n-heptane.
- the base used in step 2-a is selected from N,N-diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, DBU, DBN, DABCO and the like.
- Preferred solvent is N,N-diisopropylethylamine.
- the base used in step 3-a is selected from imidazole, N,N-diisopropylethylamine, triethylamine, pyridine, DBU, DBN, DABCO and the like.
- Preferred base is Imidazole.
- Compound (V-a) is dissolved in one or more solvent in presence of base to obtain compound of (Vl-a).
- One or more solvent used in step 4-a is selected from dimethyl sulfoxide, N,N- dimethylformamide, toluene, tetrahydrofuran, 1,4-dioxane, dimethyl ether, Acetone, tetrahydrofuran,, n-hexane, n-heptane and the like.
- Preferred solvent is dimethyl sulfoxide.
- the base used in step 4-a is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, or sodium pentoxide, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodamide and the like.
- Preferred base is potassium hydroxide.
- one or more solvent used in step 5-a is selected from water, methanol, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, acetonitrile, ethyl acetate, toluene, dichloromethane, n-hexane, n-heptane and the like.
- Preferred solvent is ethanol and water.
- the base used in step 5-a is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tertiarybutoxide, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodamide and the like.
- Preferred base is potassium hydroxide.
- Part-A Reacting compound (VII-a) with isobutyl chloroformate in presence of base and one or more solvent to obtain filterate;
- Part-B Sodium borohydride is dissolved in one or more solvent. Adding filterate obtained from Part-A to the reaction mixture to obtain compound (VIII-)a.
- one or more solvent used in step 6-a is selected from ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, methyl tert-butyl ether, water, ethyl acetate and the like.
- Preferred solvent is tetrahydrofuran.
- the base used in step 6-a is selected N-methyl morpholine, Diisopropylethyl amine, triethyl amine, potassium hydroxide, pyridine, DBU, DBN, DABCO and the like.
- Preferred base is N- methyl morpholine.
- one or more solvent used in step 7-a is selected from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, n-hexane, n- heptane, cyclohexane and the like.
- Preferred solvent is dichloromethane.
- the oxidizing agents used in step 7-a is selected from pyridinium chlorochromate, Pyridinium Dichromate, chromium trioxide, Collins reagent, Swern oxidation and the like.
- Preferred oxidizing agent is pyridinium chlorochromate.
- Compound (IX-a) is dissolved in one or more solvent in presence of base.
- Compound (X-a) is dissolved in one or more solvent and obtained solution was adding in the mixture of compound (IX-a) to obtain compound (Xl-a).
- one or more solvent used in step 8-a is selected from N,N-dimethylformamide, dimethylsulfoxide, toluene, ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, methyl tert-butyl ether and the like.
- Preferred solvent is N,N-dimethylformamide.
- the base used in step 8-a is selected from sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydride, potassium tert-butoxide or sodium pentoxide and the like.
- Preferred base is sodium hydride.
- Step 9-a Preparation of compound (XII-a):
- one or more solvent used in step 9-a is selected from dimethylformamide, dimethylsulfoxide, toluene, ethers, methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t- butyl alcohol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, methyl tert-butyl ether, n-hexane, n-heptane and the like.
- Preferred solvent is dimethylsulfoxide.
- Suitable temperature for heated used in step 9-a is 50°C to 100°C.
- Step 10-a Preparation of compound (XlV-a)
- Compound (XII-a ) is dissolved in one or more solvent in present of base.
- Compound (XIII-)a is dissolved in one or more solvent and obtained solution was adding dropwise in the mixture of compound (XII- a) to obtain compound (XIV- a).
- one or more solvent used in step 10-a is selected from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, cyclohexane, n- hexane and the like.
- Preferred solvent is N,N-dimethylformamide.
- the base used in step 10-a is selected from N-methyl morpholine, N,N-Diisopropylethylamine, triethyl amine, pyridine, DBU, DBN, DABCO, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydride, potassium tert-butoxide, or sodium pentoxide and the like.
- Preferred base is sodium hydride.
- Step 11 -a Preparation of compound (XV-a)
- Compound (XlV-a) is dissolved in one or more solvent. Adding reagent in a mixture of compound (XlV-a) to obtain compound (XV-a).
- one or more solvent used in step 11 -a is selected from dichloromethane, dichloroethane, chlorobenzene, toluene, xylene, ethylbenzene, pentane, n-hexane, heptane, cyclohexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethylether, methyl tert-butyl ether, ethyl acetate, tetrahydrofuran, acetone, N,N-dimethylformamide and the like.
- Preferred solvent is dichloromethane.
- the reagent used in step 11 -a is selected from trifluoroacetic acid, hydrochloric acid, Methane sulphonic acid, Acetic acid, formic acid and the like. Preferred reagent is trifluoroacetic acid.
- Compound (XV-a) is dissolved in one or more solvent in presence of base and reagent. Adding one or more reagent to the reaction mixture of compound (XV-a) to obtain compound (I-a).
- one or more solvent used in step 12-a is selected from water, dichloromethane, dichloroethane, chlorobenzene, toluene, xylene, ethylbenzene, pentane, n-hexane, n-heptane, cyclohexane, tetrahydrofuran, 1, 4-dioxane, diisopropyl ether, diethylether or methyl terttertbutyl ether and the like.
- Preferred solvent is water.
- the base, used in step 12-a is selected from triethylamine, Diisopropylethylamine, pyridine, DBU, DBN, DABCO and the like.
- Preferred base is Triethylamine.
- the reagent used in step 12-a is selected from p-formaldehyde, sodium borohydride, Pd/C, Raney nickel, vitride or lithium aluminium hydride and the like.
- Preferred reagent is p- formaldehyde and sodium borohydride.
- one or more solvent used in purification is selected from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, water, dimethylformamide, n-hexane, tetrahydrofuran, 1, 4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether and the like.
- Preferred solvent is acetone.
- the compound of formula (I-a) either in crystalline or amorphous or partially crystalline form.
- the crystalline Form I of formula (I-a) has a powder X-ray diffraction pattern as given in Figure 1.
- the crystalline Form I of formula (I-a) has a powder X-ray diffraction pattern having a peak at about 5.9 ⁇ 0.2, 10.9 ⁇ 0.2, 17.3 ⁇ 0.2, 17.8 ⁇ 0.2, 18.2 ⁇ 0.2, 20.1 ⁇ 0.2 and 20.6 ⁇ 0.2 degrees 2-theta.
- the crystalline Form I of formula (La) has a powder X-ray diffraction pattern having a peak at about 17.8 ⁇ 0.2 degrees 2-theta;
- the present invention provides process for the preparation of crystalline Form I of formula (La).
- the process comprises:
- solvent used in step (i) is selected from acetonitrile, toluene, ethyl acetate, dichloromethane, tetrahydrofuran, acetone, water, dimethylformamide, n-hexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether and the like.
- the crystalline Form II of formula (La) has a powder X-ray diffraction pattern as given in Figure 2.
- the crystalline Form II of formula (La) has a powder X-ray diffraction pattern having a peak at about 7.4 ⁇ 0.2, 10.5 ⁇ 0.2, 16.4 ⁇ 0.2, 19.6 ⁇ 0.2, 20.4 ⁇ 0.2 and 20.9 ⁇ 0.2 degrees 2-theta.
- the present invention provides process for the preparation of crystalline Form II of formula (La).
- the process comprises:
- step (i) dissolving compound of formula (La) in one or more solvent or a mixture of solvent to obtain crystalline compound of formula (La).
- solvent used in step (i) is selected from methanol, ethanol, Isopropyl alcohol, toluene, ethyl acetate, dichloromethane, acetone, water, and the like.
- the crystalline Form III of formula (La) has a powder X-ray diffraction pattern as given in Figure 3.
- the crystalline Form III of formula (La) has a powder X-ray diffraction pattern having a peak at about 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 13.1 ⁇ 0.2, 18.2 ⁇ 0.2, and 19.3 ⁇ 0.2 degrees 2-theta.
- the present invention provides process for the preparation of crystalline Form III of formula (La).
- the process comprises: (i) dissolving compound of formula (I-a) in one or more solvent or a mixture of solvent to obtain crystalline Form III of formula (I-a).
- solvent used in step (i) is selected from methanol, ethanol, isopropyl alcohol, dichloromethane, water, diisopropyl ether, diethyl ether, and methyl tert-butyl ether and the like.
- the amorphous form of formula (I-a) has a powder X-ray diffraction pattern as given in Figure 4.
- the present invention provides process for the preparation of amorphous form of formula (I-a).
- the process comprises:
- step (ii) spray drying of feed stock solution from step (i) to get amorphous compound of formula (I-a).
- one or more solvent used in step (i) is selected from dichloromethane, tetrahydrofuran, acetone, water, n-hexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, methyl tert-butyl ether and the like.
- the compound of formula (A) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (B) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- Compound C In an embodiment the compound of formula (C) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (D) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (D) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- Compound F In an embodiment the compound of formula (F) is controlled in formula (La) with the limit of 0.01% to 2.0%.
- the compound of formula (G) is controlled in formula (La) with the limit of 0.01% to 2.0%.
- the compound of formula (H) is controlled in formula (La) with the limit of 0.01% to 2.0%.
- Compound I In an embodiment the compound of formula (I) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- the compound of formula (J) is controlled in formula (I-a) with the limit of 0.01% to 2.0%.
- Example 1 Process for preparation of ethyl L-alaninate hydrochloride - compound of formula (Ill-a).
- Ethyl L-alaninate hydrochloride (Ill-a) (5.1 Kg, 33.2 mol), diisopropylethyl amine (12.86 kg, 99.60 mol), l-Bromo-3 -chloropropane (18.29 kg, 116.20 mol) and tetrabutylammonium bromide (0.535 Kg, 1.660 mol) were added in acetonitrile (20.4 L) in 150 L SSR at room temperature. Reaction mixture was stirred for 72 h at room temperature and further quenched with 20% aqueous citric acid solution (127.5 L) to bring pH 3 to 4.
- Reaction mixture was then washed with n-Heptane (20.4 L x 2) and aqueous layer was then basify with 4 N sodium hydroxide solution (95 L) to bring pH 9 to 10.
- Aqueous layer was extracted with methyl tertiary butyl ether (25.5 L x 2).
- Organic layer was washed with 10% aqueous sodium bicarbonate solution (15.5 L) and 10% sodium chloride solution (10.2 L).
- Organic layer containing ethyl (3-chloropropyl)-L- alaninate (IV-a) was used in next reaction without any further purification.
- Example 3 Process for Preparation of ethyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)- L-alaninate - compound of formula (V-a)
- Ethyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-L-alaninate (V-a) (5 Kg, 17.01 mol) was added in dimethyl sulfoxide (25 L) in a 50 L SSR, at room temperature. Reaction mixture was cooled at 20 to 25 °C and potassium hydroxide (2.86 Kg, 51.05 mol) was added at 20 to 25°C and further reaction mixture was stirred for 3 h at room temperature. The reaction mixture was dump in to water (125 L) and aqueous layer was extracted with ethyl acetate (25 L x 3).
- reaction mixture was quenched with water (124 L) and aqueous layer was washed with dichloromethane (31 L x 2) and then aqueous layer was acidifying with 5 N aqueous hydrochloric acid (52.7 L) to bring pH 3 to 4.
- Aqueous layer was extracted with ethyl acetate (62 L x 1 and 31 L x 2). Combined all organic layer was concentrated in vacuum to get crude solid product which was recrystallized with n-heptane (25.6 L) followed by cyclohexane (24 L).
- Example 8 Process for Preparation of tert-butyl (R,E)-2-(2-(N-(tert- butoxycarbonyl)sulfamoyl)vinyl)-2-methylpyrrolidine-l-carboxylate (Xl-a) tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (IX-a) (3.07 Kg, 7.76 mol) was added in N,N-Dimethyl formamide (23 L) in a 100 L GAR at room temperature under Nitrogen gas atmosphere, It was cooled to 0 to 5 °C and added NaH (0.988 Kg, mol). It was gradually warmed to 25 °C and stirred for 30 min.
- Xl-a tert-butyl (R,E)-2-(2-(N-(tert- butoxycarbonyl)sulfamoyl)vinyl)-2-methylpyrrolidine-l-carboxylate (Xl-a
- Aqueous layer was washed with Diisopropylether (23 L) and then aqueous layer was acidify with 50% aqueous citric acid (11 L) to bring pH 3.5 to 4.5.
- Aqueous layer was extracted with ethyl acetate (34.5 L x 1 and 23 L x 2).
- Organic layer was washed with water (23 L x 2), 5% aqueous sodium bicarbonate solution (11.5 L x 2) followed by 10% brine solution (11.5 L).
- Example 10 Process for Preparation of tert-butyl (R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-l-carboxylate (XlV-a)
- Example 11 Process for Preparation of (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-l-sulfonamide 2,2,2-trifluoroacetate (XV- a)
- Example 12 Process for Preparation of Form I of (R,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N- ((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-l-sulfonamide (I-a)
- Example - 15 Process for preparation of Form-Ill of (R,E)-2-(l,2-dimethylpyrrolidin-2- yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-l-sulfonamide (I-a)
- Example - 16 Process for preparation of amorphous form of (R,E)-2-(l,2- dimethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-l- sulfonamide (I-a)
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Abstract
La présente invention concerne un procédé amélioré pour la préparation de composés à base de sulfonylurée de formule générale (I). Plus spécifiquement, la présente invention concerne un procédé amélioré pour la préparation d'un composé de formule (I-a). La présente invention concerne également certaines nouvelles impuretés générées pendant le processus.
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Citations (2)
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EP2420234B1 (fr) * | 2005-04-11 | 2013-07-10 | Abbott Laboratories | 1h-benzimidazole-4-carboxamides substitues avec un carbone quaternaire en position 2 tenant lieu d'inhibiteurs puissants de parp utilises pour le traitement de cancer |
WO2020148619A1 (fr) * | 2019-01-14 | 2020-07-23 | Cadila Healthcare Limited | Nouveaux dérivés de sulfonylurées substitués |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP2420234B1 (fr) * | 2005-04-11 | 2013-07-10 | Abbott Laboratories | 1h-benzimidazole-4-carboxamides substitues avec un carbone quaternaire en position 2 tenant lieu d'inhibiteurs puissants de parp utilises pour le traitement de cancer |
WO2020148619A1 (fr) * | 2019-01-14 | 2020-07-23 | Cadila Healthcare Limited | Nouveaux dérivés de sulfonylurées substitués |
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